Leukemia is a bone marrow cancer involving developing white blood cells and often is associated with specific, recurrent chromosome translocations and inversions that generate fusion genes, which play critical roles in leukemogenesis. In this project, targeted treatments are being developed for a subgroup of leukemia based on current understanding of how leukemia develops at the molecular level. The core binding factor (CBF) subgroup of leukemia contains CBF fusion genes that have been shown to play critical roles in leukemia development. Current treatments for CBF leukemia are not optimal, with long-term survival at 50 percent. The research team conducted a small chemical library screen to find inhibitors that block CBF protein interactions. Through biochemical, cell culture and animal model studies, they identified three chemically related lead compounds. One of these compounds showed leukemia reduction capability similar to standard chemotherapy drugs in preliminary studies in a mouse CBF leukemia model. TRND researchers have successfully optimized and demonstrated the utility of the animal disease model and showed for the first time that the initial lead compound is effective in the model as monotherapy. TRND scientists performed medicinal chemistry optimization to identify a compound with significantly improved pharmacokinetics and tolerability after repeat dosing in mice. The collaborator developed an improved in vitro efficacy assay, using cells extracted from bone marrow, to support the medicinal chemistry. Currently, the optimized lead compound is being evaluated in the animal disease model.